Mental retardation (MR) is a pathological condition diagnosed by a low intelligence quotient (IQ<70). MR affects 2-3% of the total population and is considered one of the most costly diseases in Western countries. Although human genetic studies have identified a plethora of MR candidate genes whose protein products are implicated in diverse neuronal processes, mechanisms by which many of these MR candidate genes regulate cognitive functions remain largely unclear. Epigenetic regulation has recently emerged as a potentially crucial mechanism in MR. Epigenetic regulation utilizes chromatin modifications (DNA methylation and histone covalent modifications) to produce stable changes in gene transcriptional activity, which impact development and physiology of the organism. We recently identified and characterized two histone demethylases, SMCX and PHF8, both causing mental retardation when mutated in humans, suggesting an important role for histone methylation dynamics in human cognitive function. Importantly, we have recently generated mice carrying a conditional allele of Smcx. Ablation of Smcx in the brain causes cognitive defects in associative memory and reduced expression of genes regulated by neuronal activity in amygdala. One of the main goals of this application is to understand the cellular and molecular mechanism of action of Smcx in learning and memory. Specifically, we will investigate if Smcx plays a general role in the formation of various memories, including short versus long term memory. We will investigate the cellular basis for the memory deficits associated with Smcx loss. Specifically, we will determine whether loss of Smcx impacts neural development as well as synaptic/dendritic structure and function. We will also carry out electrophysiological studies to determine the impact of Smcx loss on long-term potentiation and depression. These experiments will provide novel insights into the cellular mechanism by which Smcx regulates memory formation. We will also investigate the molecular mechanism by which Smcx regulates learning and memory. We will address this question by identifying, at genome-wide level, Smcx binding sites and gene expression networks regulated by Smcx. Based on our preliminary data, special attentions will be given to enhancers where Smcx may contribute to the generation of H3K4me1 (a defining histone modification with unclear functional role) via its demethylase activity and thus contribute to activity-dependent neuronal gene transcription during memory formation. Findings will not only provide significant molecular insights into how SMCX regulates cognition but also shed light on the functional role of H3K4me1 at enhancers, which remained an outstanding question in the epigenetic field. Taken together, the proposed studies will provide significant new insights into epigenetic mechanisms that control cognitive function and behavior, and, when go awry, cause debilitating human diseases such as MR. PUBLIC HEALTH RELEVANCE: This application studies epigenetic mechanisms that regulate neuronal development and cognitive function. When these mechanisms go awry, they can lead to debilitating human disease such as mental retardation. Findings from the proposed studies will lay important conceptual frameworks for future therapeutic intervention.